Allogeneic marrow transplantation from HLA genotypically identical siblings have become life-saving therapy for patients with various congenital and acquired diseases of the immune and hematopoietic systems. Graft-versus-host disease (GVHD), however, remains a significant cause of morbidity and mortality. Nonspecific immune suppression developed through empirical trials has provided increasingly better GVHD control, but these agents are potentially toxic, they delay immune reconstitution and increase the risk of infection. Less than 30% of patients have an HLA identical sibling and many are denied the opportunity for a potentially curative treatment for otherwise fatal disease. The development of a national registry of potential marrow donors has made it possible to access a centralized file of more than 1.5 million HLA typed volunteers. GVHD is increased in both incidence and severity in unrelated donor transplants. This may be explained by an inability to achieve sufficient donor and recipient HLA matching, however incompatibility for non-HLA minor histocompatibility antigens (mHA) may also play a role. Improved HLA typing alone will not solve all problems related to donor selection because the extreme nature of HLA polymorphism in human populations dictates that many patients will never find a perfectly matched donor. Successful management of these patients will depend on improving our understanding of T cell responses to alloantigen and development of more rational effective approaches to achieving tolerance. There are four scientific projects in this Program Project grant, and one administrative and shared resources core. The first Project is aimed at discovering new polymorphic genes residing within the HLA class I region, ad characterizing the function and expression of these nonclassical class I genes. The second Project is aimed at defining the antigen presenting function of human CD34+ stem cells and peripheral blood progenitor cells, and identifying costimulatory molecules required for T cell responses to alloantigens expressed by hematopoietic cells. The third Project involves studies of donor T cell responses to host the classical diversity of this response and the identification of T cells responsible for GVHD. The fourth Project is directed to studies of peptide ligands presented by class I HLA-A, B and C molecules, the peptide motifs that define alloantigens and the role that peptides selection may play in determining the repertoire of the T cell response in marrow allografts.